Acute Pancreatitis (AP) is a potentially lethal inflammatory disease of the pancreas. Its pathogenesis remains obscure and is involved in a process of acute inflammation and necrosis in the pancreas, with variable involvement of regional tissues or organ systems that leads to a systemic inflammatory response. AP contributes to thousands of annual hospital admissions and consecutive complications. In the US alone, >300,000 patients are hospitalized annually with AP leading to 7,200 deaths. In the majority of patients, the condition is mild, but 25% of patients suffer a severe attack, and between 30 and 50%of the patients will die. The most common causes of AP is the presence of gallstones and heavy alcohol (60%-80%) use that cause inflammation and necrosis of the pancreas. Other causes include trauma, infections, medications, and tumors of the pancreas. For mild cases, standard therapy and current treatments are non-steroidal anti-inflammatory drugs (NSAID) and corticosteroids, antibiotics, and nutrition supplements. Standard therapy for patients with severe disease includes early invasive monitoring and resuscitation, prophylactic antibiotics, nutrition, and serial CT scanning to identify infection and necrosis. There is no single effective therapeutic strategy for severe acute pancreatitis. Recently, despite the use of less invasive techniques, complications following debridement of necrotic pancreatic tissue are still common and the mortality rate with severe AP is still high. It also inflicts a heavy economic burden;the direct cost in the US alone is more than $2 billion annually. Hence there is a critical need for effective and affordable non-surgical therapy for AP. Poly (ADP-ribose) polymerase (PARP), a nuclear enzyme, plays an important role in the pathogenesis of AP. Recent studies have shown that oxygen-derived free radicals play a crucial role in the pathogenesis of AP. Oxidative stress caused by free radicals and activation of PARP has been proposed as a common mechanism for pancreatic injury in alcohol, gallstone and ischemic pancreatitis as well as in other experimental models of AP. PARP overactivation, depletes the intracellular concentration of NAD+ and ATP, thus leading to cellular dysfunction and cell death. One of the most exciting areas of research for the treatment of pancreatic injury is to inhibit PARP activation. Using a product discovery engine comprising 3-D molecular modeling, we successfully identified two novel small molecules that inhibit PARP activity in vitro and exerts protective effects in in vivo models of AP and toxic injury. Our therapeutic strategy is designed to bring one of the best PARP inhibitor to further study and bring to clinical trials to attenuate patient morbidity and mortality associated with severe AP. PUBLIC HEALTH RELEVANCE: Pancreatitis (AP) is an inflammatory and necrotic disease of the pancreas and severe AP is associated with systemic inflammatory response with high morbidity and mortality. Poly (ADP-ribose) polymerase (PARP), a nuclear enzyme, plays an important role in the pathogenesis of AP. DNA damage by reactive oxygen/nitrogen free radicals in pancreatic injury and consequent over-activation of PARP promotes pancreatic cellular dysfunction/cell death leading to AP. Current therapeutic methods are insufficient for the treatment of severe AP. One of the most exciting areas of research for the treatment of pancreatic injury is to inhibit PARP activation. Using a 3-D molecular modeling, we successfully identified two novel PARP inhibitors. Our therapeutic strategy in the current project is to test our lead PARP inhibitors in two invivo models of AP and identifify one of the best PARP inhibitor to further studies in Phase II and potentially a clinical product.